4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de] quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid salt crystal forms

ABSTRACT

The present invention relates to toluenesulfonic acid addition salt crystals of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone, and methods of using such crystals as 5-hydroxytryptamine 2 receptor agonists and antagonists in treating disorders of the central nervous system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 14/177,689, filed on Feb.11, 2014, which is a divisional of Ser. No. 12/922,056, now granted asU.S. Pat. No. 8,648,077, which was filed Sep. 10, 2010 under 35 U.S.C§371 which claims benefit to PCT Application No. PCT/US2009/001608,filed on Mar. 12, 2009 which claims the benefit of U.S. ProvisionalPatent Application No. 61/036,069, filed Mar. 12, 2008, the contents ofeach of which are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to toluenesulfonic acid addition saltcrystals of specific substituted heterocycle fused gamma-carbolines, themethod of making and using such crystals.

BACKGROUND OF THE INVENTION

Substituted heterocycle fused gamma-carbolines and theirpharmaceutically acceptable salts are represented by the core structureshown in Formula 1 J:

These compounds are disclosed in WO 2000/77010; WO 2000/77002; WO2000/77001; U.S. Pat. Nos. 6,713,471; 6,552,017; 7,081,455; 6,548,493,7,071,186; Reissue U.S. Pat. Nos. 39,680; 39,679; and U.S. ProvisionalApplication No. 60/906,473, the contents of each of which are hereinincorporated by reference in their entirety. These compounds have beenfound to be useful as 5-HT₂ receptor agonists and antagonists used intreating disorders of the central nervous system including a disorderassociated with 5HT2C or 5HT2A receptor modulation selected fromobesity, anorexia, bulimia, depression, a anxiety, psychosis,schizophrenia, migraine, obsessive-compulsive disorder, sexualdisorders, depression, schizophrenia, migraine, attention deficitdisorder, attention deficit hyperactivity disorder, obsessive-compulsivedisorder, sleep disorders, conditions associated with cephalic pain,social phobias, gastrointestinal disorders such as dysfunction of thegastrointestinal tract motility.

As a free base, substituted heterocycle fused gamma-carbolines exist inliquid form and are susceptible to N-oxidation and/or degradation. Suchunstable characteristics could render these compounds undesirable aspharmaceutical products. The prior art discloses a large number ofsubstituted heterocycle fused gamma-carboline derivatives in free baseform as well as a large number of pharmaceutically acceptable salts,including hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like. Of the large numbers of possible pharmaceuticallyacceptable salt compounds disclosed in the prior art, none were shown tohave particular stability or desired properties. Because manypharmaceutical compounds can exist in different physical forms (e.g.,liquid or solid in different crystalline, amorphous, polymorphous,hydrate or solvate forms) which can vary the stability, solubility,bioavailability or pharmacokinetics (absorption, distribution,metabolism, excretion or the like) and/or bioequivalency of a drug, itis of critical importance in pharmaceutical development to identify apharmaceutical compound of optimal physical form (e.g., free base orsalt in solid, liquid, crystalline, hydrate, solvate, amorphous orpolymorphous forms).

SUMMARY OF THE INVENTION

We have surprisingly found that a particular substituted heterocyclefused gamma-carboline is especially stable in toluenesulfonic acidaddition salt form and is especially advantageous in the preparation ofgalenic formulations of various and diverse kind. The present inventiontherefore provides4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8 (7H)-yl)-1-(4-fluorophenyl)-1-butanonetosylate salt in solid form (“Solid Salt of the Present Invention”). Inparticular, the present invention provides4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanonetosylate salt crystal (“Salt Crystals of the Present Invention”). It hasbeen surprisingly found that the Salts Crystals of the Present Inventionare especially stable and preferred for galenic and/or therapeutic use.The invention therefore provides the following:

-   -   1.1 Salt Crystals of the Present Invention in dry crystalline        form;    -   1.2 Salt Crystals of the Present Invention or formula 1.1, in        needle form;    -   1.3 Salt Crystals of the Present Invention or formula 1.1, in        flake form (e.g., thin flakes or flake fragments);    -   1.4 Salt Crystals of the Invention or any of formulae 1.1-1.2,        wherein said Salt Crystals are in a single crystal form and are        free or substantially free of any other form, e.g., free or        substantially free, e.g., less than 10 wt. %, preferably less        than about 5 wt. %, more preferably less than about 2 wt. %,        still preferably less than about 1 wt. %, still preferably less        than about 0.1%, most preferably less than about 0.01 wt. % of        amorphous form;    -   1.5 Salt Crystals of the Invention or any of formulae 1.1-1.4,        wherein said Salt Crystals are in a single crystal form and are        free or substantially free of any other form, e.g., less than 10        wt. %, preferably less than about 5 wt. %, more preferably less        than about 2 wt. %, still preferably less than about 1 wt. %,        still preferably less than about 0.1%, most preferably less than        about 0.01 wt. % of other crystal forms;    -   1.6 Salt Crystals of the Invention or any of formulae 1.1-1.4,        wherein said Salt Crystals are in a single crystal form and are        free or substantially free of any other form, e.g., less than 10        wt. %, preferably less than about 5 wt. %, more preferably less        than about 2 wt. %, still preferably less than about 1 wt. %,        still preferably less than about 0.1%, most preferably less than        about 0.01 wt. % of amorphous and other crystal forms;    -   1.7 Salt Crystals of the Invention or any of formulae 1.1-1.6,        wherein said Salt Crystals are in a non-solvate or non-hydrate        form;    -   1.8 Salt Crystals of the Invention or any of formulae 1.1-1.7,        wherein said Salt Crystals are in a non-solvate and non-hydrate        form;    -   1.9 Salt Crystals of the Present Invention or any of formulae        1.1-1.8, wherein said Salt Crystals exhibit an X-ray powder        diffraction pattern comprising at least two 2-theta values        selected from those set forth below (“Crystal Form A”):

Position Relative Intensity (°2θ) D-spacing (Å) (%) 5.68 15.543 100.012.11 7.303 26.0 16.04 5.520 22.3 17.03 5.202 66.8 18.16 4.882 21.619.00 4.668 20.8 21.67 4.097 15.7 22.55 3.940 23.9 23.48 3.786 18.924.30 3.660 23.5

-   -   1.10 Salt Crystals of the Present Invention or any of formulae        1.1-1.9, wherein said Salt Crystals exhibit an X-ray powder        diffraction pattern comprising at least five 2-theta values        selected from those set forth below (“Crystal Form A”):

Position Relative Intensity (°2θ) D-spacing (Å) (%) 5.68 15.543 100.012.11 7.303 26.0 16.04 5.520 22.3 17.03 5.202 66.8 18.16 4.882 21.619.00 4.668 20.8 21.67 4.097 15.7 22.55 3.940 23.9 23.48 3.786 18.924.30 3.660 23.5

-   -   1.11 Salt Crystals of the Present Invention or any of formulae        1.1-1.10, wherein said Salt Crystals exhibit an X-ray powder        diffraction pattern substantially as herein set forth below        (“Crystal Form A”):

Position Relative Intensity (°2θ) D-spacing (Å) (%) 5.68 15.543 100.012.11 7.303 26.0 16.04 5.520 22.3 17.03 5.202 66.8 18.16 4.882 21.619.00 4.668 20.8 21.67 4.097 15.7 22.55 3.940 23.9 23.48 3.786 18.924.30 3.660 23.5

-   -   1.12 Salt Crystals of the Invention or any of formulae 1.1-1.11,        wherein said Salt Crystals exhibit an X-ray powder diffraction        pattern substantially as herein set forth in Table 4 and/or FIG.        7 (“Crystal Form A”);    -   1.13 Salt Crystals of the Invention or any of formulae 1.1-1.11,        wherein said Salt Crystals exhibit an X-ray powder diffraction        pattern substantially as herein set forth in FIG. 7A (“Crystal        Form A”);    -   1.14 Salt Crystals of the Present Invention or any of formulae        1.1-1.8, wherein said Salt Crystals exhibit an X-ray powder        diffraction pattern comprising at least two 2-theta values        selected from those set forth 7B;    -   1.15 Salt Crystals of the Present Invention or any of formulae        1.1-1.8, wherein said Salt Crystals exhibit an X-ray powder        diffraction pattern substantially as herein set forth in FIG. 7B        (“Crystal Form A”);    -   1.16 Salt Crystals of the Invention or any of formulae 1.1-1.15,        wherein said Salt Crystals exhibit a differential scanning        calorimetry (DSC) pattern comprising a single endotherm with an        onset temperature range of about 178° C.-179° C. (e.g., 178.8°        C.) (“Crystal Form A”);    -   1.17 Salt Crystals of the Invention or any of formulae 1.1-1.16,        wherein said Salt Crystals exhibit a differential scanning        calorimetry (DSC) pattern comprising a single endotherm with a        peak temperature range of about 180° C.-181° C. (e.g., 180.8°        C.) (“Crystal Form A”);    -   1.18 Salt Crystals of the Invention or any of formulae 1.1-1.17,        wherein said Salt Crystals exhibit a differential scanning        calorimetry (DSC) pattern comprising a single endotherm with an        enthalpy of transition (ΔH) of about 60-65 J/g, preferably about        62-64 J/g, most preferably about 63-64 J/g, e.g., about 63 J/g        (e.g., 63.6 J/g) (“Crystal Form A”);    -   1.19 Salt Crystals of the Invention or any of formulae 1.1-1.18,        wherein said Salt Crystals exhibit a differential scanning        calorimetry (DSC) pattern substantially as herein setforth in        FIG. 8 (“Crystal Form A”);    -   1.20 Salt Crystals of the Invention or any of formulae 1.1-1.19,        wherein said Salt Crystals exhibit a differential scanning        calorimetry (DSC) pattern as herein setforth in FIG. 8 (“Crystal        Form A”);    -   1.21 Salt Crystals of the Invention or any of formulae 1.1-1.20,        wherein said Salt Crystals exhibits a thermogravimetric analysis        profile comprising two regions of weight loss with a total        weight loss of about 0.5% (e.g., 0.46%) through 200° C.        (“Crystal Form A”);    -   1.22 Salt Crystals of the Invention or any of formulae 1.1-1.21,        wherein said Salt Crystals exhibits a thermogravimetric analysis        profile substantially as herein setforth in FIG. 8 (“Crystal        Form A”);    -   1.23 Salt Crystals of the Invention or any of formulae 1.1-1.22,        wherein said Salt Crystals exhibits a thermogravimetric analysis        profile as herein setforth in FIG. 8 (“Crystal Form A”);    -   1.24 Salt Crystals of the Invention or any of formulae 1.1-1.23,        wherein said Salt Crystals have an infrared spectrum comprising        at least two bands, e.g., at least five bands selected from the        bands as set forth in Table 1 (“Crystal form A”);    -   1.25 Salt Crystals of the Invention or any of formulae 1.1-1.24,        wherein said Salt Crystals exhibit a Fourier Transform Infrared        Spectrometry Band pattern substantially as herein set forth in        Table 1 (“Crystal Form A”);    -   1.26 Salt Crystals of the Invention or any of formulae 1.1-1.25,        wherein said Salt Crystals have a melting point in the range of        about 176° C. to about 181° C.    -   1.27 Salt Crystals of the Invention or any of formulae 1.1-1.26        wherein said Salt Crystals exhibit any combination of        characterisitics as described in 1.1-1.26 (“Crystal Form A”);    -   1.28 Crystals of the Invention or any of formulae 1.1-1.8,        wherein said Salt Crystal exhibit an X-ray powder diffraction        pattern substantially as herein set forth in Table 5 or FIG. 9        or 10 (“Crystal Form B”);    -   1.29 Crystals of the Invention when made by any of processes        2.1-2.9.

The invention also provides the following:

-   -   2.1 A process for the production of Salt Crystals of the Present        Invention, e.g., any of formulae 1.1-1.28, which process        comprises the steps of:        -   a) reacting            4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:            4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone            free base (“Free Base of the Present Invention”) with            p-toluenesulfonic acid; or        -   b) dissolving            4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:            4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone            toluenesulfonic acid addition salt (“Salt of the Present            Invention”) in a solvent; and        -   c) optionally cooling said reaction mixtures, e.g., to            0°-25° C.;    -   2.2 Process 2.1, wherein said solvent is selected from        C₁₋₄alcohol (e.g., methanol, ethanol, isopropyl alcohol),        acetone, ethyl acetate, n-propyl acetate, acetonitrile,        tetrahydrofuran, butanone, heptane, hexane, water, toluene and        mixtures thereof;    -   2.3 Process 2.1 or 2.2, wherein said solvent is selected from        C₁₋₄alcohol (e.g., methanol, ethanol, isopropyl alcohol),        acetone, ethyl acetate, n-propyl acetate, acetonitrile,        tetrahydrofuran and mixtures thereof;    -   2.4 Process 2.1, 2.2 or 2.3, wherein said solvent is ethanol;    -   2.5 Process 2.1, 2.2 or 2.3, wherein said solvent is 2-propanol;    -   2.6 Any of Processes 2.1-2.5, which process further comprises        the step of adding an anti-solvent;    -   2.7 Process 2.6, wherein said anti-solvent is selected from        butanone, hexane, heptane, toluene and water;    -   2.8 A process for the production of Salt Crystal Form A, e.g.,        any of formulae 1.1-1.27, comprising the step of        -   (a) reacting            4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:            4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone            free base with p-toluenesulfonic acid, e.g.,            p-toluenesulfonic acid monohydrate, in isopropyl alcohol,            preferably in 2-5 mL, preferably 3.5 mL of isopropanol per            gram of said free base to form the salt crystals;        -   (b) optionally cooling said reaction mixture, e.g., cooling            to 0°-25° C.    -   2.9 A process for the production of Salt Crystal Form B        comprising the step of        -   (a) reacting            4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:            4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone            with p-toluenesulfonic acid e.g., p-toluenesulfonic acid            monohydrate in ethyl alcohol, preferably in 2-5 mL,            preferably 3 mL of ethanol per gram of said free base to            form the salt crystals; and        -   (b) optionally cooling said reaction mixture, e.g., cooling            to 0°-25° C.    -   2.10 A pharmaceutical composition comprising Salt Crystals of        the Present Invention, e.g., any of formulae 1.1-1.29, as active        ingredient, together with a pharmaceutically acceptable diluent        or carrier;    -   2.11 A pharmaceutical composition comprising Salt Crystals of        the Present Invention, e.g., any of formulae 1.1-1.29, as active        ingredient, together with a pharmaceutically acceptable diluent        or carrier wherein said composition is predominantly, or is        entirely or substantially entirely, in dry crystalline form;    -   2.12 A Crystalline Solid of the Present Invention, e.g., any of        formulae 1.1-1.29, for use as a pharmaceutical, e.g., for use in        method of 2.13-2.2.14, or for use in the manufacture of a        medicament for treating an indication as set forth in        2.13-2.2.14;    -   2.13 A method for the prophylaxis or treatment of a human        suffering from a disorder selected from obesity, anorexia,        bulimia, depression, a anxiety, psychosis, schizophrenia,        migraine, obsessive-compulsive disorder, sexual disorders,        depression, schizophrenia, migraine, attention deficit disorder,        attention deficit hyperactivity disorder, obsessive-compulsive        disorder, sleep disorders, conditions associated with cephalic        pain, social phobias, gastrointestinal disorders such as        dysfunction of the gastrointestinal tract motility, comprising        administering to a patient in need thereof a therapeutically        effective amount of the Salt Crystals of the Present Invention,        e.g., any of formulae 1.1-1.29 or 2.12, a pharmaceutical        composition as described in formula 2.10 or 2.11 or crystals        formed from the process as described in formula 2.1-2.9;    -   2.14 Formula 2.13, wherein said disorder is sleep disorders or        psychosis.    -   2.15 A method for the prophylaxis or treatment a disorder        selected from obesity, anorexia, bulimia, depression, a anxiety,        psychosis, schizophrenia, migraine, obsessive-compulsive        disorder, sexual disorders, depression, schizophrenia, migraine,        attention deficit disorder, attention deficit hyperactivity        disorder, obsessive-compulsive disorder, sleep disorders,        conditions associated with cephalic pain, social phobias,        gastrointestinal disorders such as dysfunction of the        gastrointestinal tract motility, comprising administering to a        patient in need thereof a therapeutically effective amount of        the Salt Crystals of the Present Invention, e.g., any of        formulae 1.1-1.29 or 2.12, a pharmaceutical composition as        described in formula 2.10 or 2.11 or crystals formed from the        process as described in any of formulae 2.1-2.9;    -   2.16 Formula 2.15, wherein said disorder is sleep disorders or        psychosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 (1/12) depicts an infrared spectrum of Salt Crystals Form Aprepared as a KBr pellet.

FIG. 2 (2/12) depicts an infrared spectrum finger print region of SaltCrystals Form A prepared as a KBr pellet.

FIG. 3 (3/12) depicts a mass spectrum of Salt Crystals Form A. Peakslabeled 1, 2 and 3 are (PEGMME 350+Na)⁺ ions.

FIG. 4 (4/12) depicts a 400-MHz proton NMR spectrum of Salt CrystalsForm A in DMSO-d6.

FIG. 5 (5/12) depicts a 100-MHz carbon NMR spectrum of Salt CrystalsForm A in DMSO-d6.

FIG. 6 (6/12) depicts a UV-Vis spectrum of Salt Crystals Form A in MeOH.The solid line depicts a spectrum of a sample having a concentration of0.12 mg/mL. The

line depicts a spectrum of a sample having a concentration of 0.0.06mg/mL. The

line depicts a spectrum of a sample having a concentration of 0.012mg/mL. The

line depicts a spectrum of a sample having a concentration of 0.0006mg/mL.

FIG. 7 (7/12) depicts X-Ray Powder Diffraction Pattern of Salt CrystalsForm A (Cu Kα Radiation).

FIG. 7A (8/12) depicts X-Ray Powder Diffraction Pattern of Salt CrystalsForm A.

FIG. 7B (9/12) depicts an X-Ray Powder Diffraction Pattern of SaltCrystals Form A. Panalytical X-Pert Pro MPD PW3040 Pro. X-ray Tube:Cu(I.54059 Å. Voltage: 15 kV. Amperage: 10 mA. Scan Range:1.01-39.98*2θ. Step Size: 0.017*2θ. Collection Time: 721 s. Scan Speed:3.2*/min. Slit: DS: ½°. SS: ¼°. Revolution Time 1.0 s. Mode:Transmission.

FIG. 8 (10/12) depicts a DSC and TGA Scans for Salt Crystals Form ATaken at a 10° C./min Scan Rate.

FIG. 9 (11/12) depicts an X-Ray Powder Diffraction Pattern of SaltCrystals Form B.

FIG. 10 (12/12) depicts an X-Ray Powder Diffraction Pattern of SaltCrystals Form B.

DETAIL DESCRIPTION

As use herein, the term “crystal” or “crystals” or “crystalline” or“crystalinic” refers to any solid that has a short or long range orderof the molecules, atoms or ions in a fixed lattice arrangement. SaltCrystals of the Present Invention may be in a single crystal form.Therefore, the Salt Crystals of the Present Invention may be in atriclinic, monoclinic, orthorhombic, tetragonal, rhobohedral, hexagonalor cubic crystal form or mixtures thereof. In particular, the SaltCrystals of the Present Invention are dry crystalline form. In anotherembodiment, the Salt Crystals of the Present Invention are in needleform. In still another embodiment, the Salt Crystals of the PresentInvention are in thin flak or flake fragment form. In a particularembodiment, the Salt Crystals of the Present Invention are substantiallyfree of other forms, e.g., free of amorphous or other crystal forms.

The term “substantially free” of other crystal forms refer to less thanabout 10 wt. %, preferably less than about 5 wt. %, more preferably lessthan about 2 wt. %, still preferably less than about 1 wt. %, stillpreferably less than about 0.1%, most preferably less than about 0.01wt. % of other crystal forms, e.g., amorphous or other crystal forms.For example, the Salt Crystals of the Present Invention is in Form A andare free or substantially free of other salt forms, e.g., greater than90 wt. % of Form A with less than 10 wt. % of the amorphous or othercrystal forms. In another example, the Salt Crystals of the PresentInvention is in Form B free or substantially free of other salt forms,e.g., greater than 90 wt. % of Form B with less than 10 wt. % of theamorphous or other crystal forms. Preferably, the Salt Crystals of thePresent Invention comprises greater than 99 wt. % a single crystal form.Similar to “substantially free”

The term “predominantly” or “substantially entirely in a single form”refers to less than about 10 wt. %, preferably less than about 5 wt. %,more preferably less than about 2 wt. %, still preferably less thanabout 1 wt. %, still preferably less than about 0.1%, most preferablyless than about 0.01 wt. % of other crystal forms, e.g., amorphous orother crystal forms. For example, the Salt Crystals of the PresentInvention is in Form A and are free or substantially free of other saltforms, e.g., greater than 90 wt. % of Form A with less than 10 wt. % ofthe amorphous or other crystal forms. In another example, the SaltCrystals of the Present Invention is in Form B free or substantiallyfree of other salt forms, e.g., greater than 90 wt. % of Form B withless than 10 wt. % of the amorphous or other crystal forms. Preferably,the Salt Crystals of the Present Invention comprises greater than 99 wt.% a single crystal form.

The term “patient” includes human or non-human.

The term “solvate” refers to crystalline solid adducts containing eitherstoichiometric or nonstoichiometric amounts of a solvent incorporatedwithin the crystal structure. Therefore, the term “non-solvate” formherein refers to salt crystals that are free or substantially free ofsolvent molecules within the crystal structures of the invention.Similarly, the term “non-hydrate” form herein refers to salt crystalsthat are free or substantially free of water molecules within thecrystal structures of the invention.

The term “amorphous” form refers to solids of disordered arrangements ofmolecules and do not possess a distinguishable crystal lattice.

The crystallinity or the morphology of the Salt Crystals of the PresentInvention may be determined by a number of methods, including, but notlimited to single crystal X-ray diffraction, X-ray powder diffraction,polarizing optical microscopy, thermal microscopy, differential scanningcalorimetry (DSC), thermogravimetric analysis (TGA), infrared adsorptionspectroscopy and Raman spectroscopy. Characterization of solvates orhydrates or lack thereof may also be determined by DSC and/or TGA.

The Solid Salt of the Present Invention may be obtained by methodsgenerally known in the art and provided in U.S. Pat. No. WO 2000/77010;WO 2000/77002; WO 200077001; U.S. Pat. Nos. 6,713,471; 6,552,017;7,081,455, 7,071,186; reissued U.S. Pat. Nos. 39,680; 39,679, e.g.,reacting the free base with the toluenesulfonic acid monohydrate in asolvent, e.g., methanol, ethanol, isopropol, ethyl acetate, methylenechloride, toluene, tetrahydrofuran, acetone, acetonitrile, water or thelike.

Crystallization methods are also well known in the art. Crystallizationof the Salt of the Present Invention may be performed by either reactingthe Free Base of the Present Invention with the toluenesulfonic acid,e.g., toluenesulfonic acid monohydrate in a solvent, e.g., C₁₋₄alcohol(e.g., methanol, ethanol, isopropyl alcohol), acetone, ethyl acetate,n-propyl acetate, acetonitrile and tetrahydrofuran and optionallycooling said solution down, e.g., to 0°-25° C.

Alternative to starting with the free base, crystallization of the Saltsof the present invention may be carried out by first dissolving thesalt, e.g., the Salts or Salt Crystals of the Current Invention, e.g.,any of formulae 1.1-1.29, in a single solvent, e.g., C₁₋₄alcohol (e.g.,methanol, ethanol, isopropyl alcohol), acetone, ethyl acetate, n-propylacetate, acetonitrile and tetrahydrofuran, preferably, optionally at anelevated temperature, e.g., greater than 25° C., e.g., at 30°-75° C.,preferably in a minimum amount of solvent (i.e., saturate the solution).Crystallization may then be induced by a number of ways, e.g., in asingle solvent system by (a) allowing the solvent to evaporate slowlyuntil crystals are formed; (b) slowing down the rate of stirring orstopping agitation completely; (c) cooling the solution down, e.g., toless than 25° C., e.g., to −10°-20° C.; (d) adding crystal seeds, e.g.,preferably, but not necessarily, the crystal of the compound which isbeing crystallized; or any combinations thereof; or in a multi-solventsystem by adding an anti-solvent(s), preferably a solvent havingdifferent polarity from the dissolution or the main solvent, e.g.,water, heptane, hexane, butanone, or toluene or mixtures thereof to asolution of the compound in a methanol, ethanol or tetrahydrofuransolvent system.

In a particular embodiment, the Salt Crystals Form A of the PresentInvention may be prepared by reacting4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanonefree base with a stoichiometric amount of p-toluenesulfonic acidmonohydrate in about 2-5 mL/g, preferably 3.5 mL/g of isopropanol pergram of the Free Base of the Present Invention and optionally coolingsaid solution until crystals start to form, e.g., to 15-25° C.Optionally, the solution may be seeded with the Salt Crystals of thePresent Invention (if available).

In another embodiment of the invention, Salt Crystals Form B may beprepared by reacting4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanonefree base in ethanol, e.g., 2-5 mL/g, preferably 3 mL/g of ethanol pergram of the free base with a stoichiometric amount of p-toluenesulfonicacid monohydrate. Optionally, another 0.5-1 mL of ethanol per gram offree base may be added and the mixture is cooled, e.g., to less than 25°C., e.g., about 10° C. until crystals are formed.

EXAMPLE 1 Preparation of the Salt Crystals Form A

Dissolve the stating material,4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone(free base) (178.4 g, 0.453 mol, 1 eq) in 2-Propanol (624.4 mL, 3.5 mLmLtg). Add charcoal (10 g) and stir the resulting mixture for 10-20minutes at room temperature. After this time, remove charcoal byfiltration. Wash the filter cake with 2-Propanol (89.2 mL, 0.5 mL/g SM).Transfer the combined filtrate to a 3 L 3-neck round bottom flaskequipped with a mechanical stirrer, nitrogen inlet, drying tube andthermocouple and placed in a cooling tub. Add the p-Toluenesulfonic acidmonollydrate (86.24 g, 0.453 mol, 1 equivalent) in one portion (reactionexotherms to 33° C., clear dark brown is observed). Cool this solutionto 15-25° C. using cold tap water. Seed the resulting solution or waituntil solids start to form (usually takes 30-60 minutes). Thickbeige/gray paste forms. Stir the resulting paste for a minimum of 3hours at 15-25° C. Collect the solids by filtration (filtration andfollowed washes are quite slow). Wash the solids with 2-Propanol (2×150mL, room temperature), and then with heptane (room temperature, 2×150mL). Dry the solids in a vacuum oven at 35° C. to a constant weight.Yield: 214 g, 0.378 mol, 83.4%. HPLC=93.2% purity. Chiral HPLC=de 100%.Melting Point 179°-181° C. The following characterization is performed:

Infrared Spectroscopy:

Two to six milligrams of sample are ground with ca. 200 mg of KBr. TheKBr pellet spectrum is obtained on a small sample of this mixturepressed into a suitable pellet using a Wilk's mini-press. The spectrumis defined by 16 scans at 2 cm⁻¹ resolution. The spectrum is disclosedin FIG. 1. Infrared spectra for Salt Crystal Form A (FIG. 1 and FIG. 2)are consistent with the tosylate Salt structure. Selected infrared bandsand their attributes are listed

in Table 1.

TABLE 1 Tentative Fourier Transform Infrared Spectrometry BandAssignments for Salt Crystals Form A BAND TENTATIVE ASSIGNMENT 2952C—H₃, wag 2824 C—H, stretch 2581 C—N, stretch 1687 C═O, stretch 1617C═C, aromatic, bend 1599 C═C, aromatic bend 1506 C═C, aromatic, stretch1328 S═O, bend 1231 S═O, bend 1162 C—N, stretch 1010 S═O, stretch 817C—H, aromatic, stretch 681 C—H, bend 569 C—F, stretch

Mass Spectrometry

Positive ion electrospray high-resolution mass spectrometry is carriedout on Salt Crystals Form A (dissolved in 1:1 Acetonitrile: Water) witha PE Sciex Q-Star hybrid quadruple/time of flight mass spectrometer. Themass spectrometer is internally calibrated using poly (ethylene gycol)monomethyl ether 350 (PPGMME 350). Two PEGMME 350 signals at m/z363.1995 and 451.2519 are used to measure a (PEGMME350+Na)+ signal. Thisgave a value of 407.2261 which compares well with the calculated valueof 407.2257. The sample signal is measured in a similar way and gives avalue of m/z 394.2299, which is 1.0 ppm from the calculated value of394.2295 for the protonated molecular ion of the free base. Theinterpretation of mass spectra (FIG. 3) Salt Crystals Form A conformswith the expected results based on the chemical structure.

NMR Spectroscopy

The 400 MGz ¹H (FIG. 4) and 100 MGz ¹³C (FIG. 5) NMR spectra for SaltCrystals Form A (Salt Crystals Form A, in DMSO-d6; TMS reference) areconsistent with the structure of4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanonetoluene sulfonic acid salt in all essential detail. Selected protonchemical shifts and coupling constants are listed in Table 2 and carbonchemical shifts are listed in Table 3.

The ¹H NMR spectrum (FIG. 4) shows signals due to 36 protons consistentwith the proposed structure. The ¹³C NMR spectrum (FIG. 5) shows 28signals consistent with the 27 unique carbons in the proposed structure.¹H spectra assignments (in Table 2) and ¹³C spectral assignments forprotonated carbons (in Table 3) are based on chemical shifts, COSYspectroscopy, HMQC spectroscopy and DEPT.

NMR spectra are recorded on a Varian 400 MHz Unityplus NMR spectrometerequipped with a 5 mm ¹H/¹⁹F/¹⁵N-³¹P switchable probe. The ¹H spectrum isrecorded using 60° rf pulses and 16 transients. The ¹³C NMR spectrum isrecorded using WALTZ proton decoupling, 60° rf pulses and 4096transients.

TABLE 2 Proton NMR Chemical Shifts for Salt Crystals Form A

δ1H* Mult† J§ Int‡ Tentative Assignment** 9.22 br s 1 25 8.04 dd 8.8 2 1 7.52 d 8 2 23 7.36 t 9.0 2  2 7.12 dd 8.4, 0.8 2 22 6.60 t 7.6 1 126.51 d 7.2 1 11 6.42 d 7.6 1 13 3.58 dd 12 1  9 3.50-3.39 m 1, 1 16, 193.36-3.30 m 1, 1, 1 15, 10, 16 3.20 m 1 17 3.16-3.00 m 7.0 2, 2, 1 6, 8,19 2.81 s 3 14 2.70 dt 10.1, 2.9 1 15 2.55 q 11.2 1  9 2.50 DMSO-d6 2.27s 3 20 2.23 br s 1 18 2.11 m 1 18 2.01 m 7.6 2  7 *Chemical shift in ppm**See structure for numbering ‡Signal integration in relative numbers ofprotons †Multiplicity; s = singlet, d = doublet, t = triplet, m =multiplet, q = quartet, br = broad §Proton-proton coupling in Hz

TABLE 3 Carbon NMR Chemical Shifts for Salt Crystals Form A Tentativeδ13C* MULT† Assignment‡ 197.2 s 5 166.3 & 163.8 d 3 145.3, 137.9, 137.3,s, s, s, 24, 21, 10a', 135.2, 133.1 & 133.1, 126.8 s, d, s 4, 13a, 10a130.9 & 130.8 d 1 128.2 s 22 125.5 s 23 120.6 s 12 115.8 & 115.6 d 2112.5 s 11 109.3 s 13 62.2 s 17 55.6 s 8 52.5 s 9 49.8 s 16 47.7 s 1943.7 s 15 39.5 DMSO-d6 38.5 s 10 37.0 s 14 34.9 s 6 21.6 s 18 20.8 s 2018.0 s 7 *Chemical shift in ppm ‡See structure for numbering†Multiplicity; s = singlet, d = doublet

Specific Rotation

The specific rotation is recorded on a Perkin Elmer model 343 Pluspolarimeter operating at the sodium D-Line (589.3 nm) and utilizing a5-s sample integration time. The sample temperature is maintained at 25°C. with a temperature controlled water-jacketed cell. The sample isprepared by dissolving ca. 475 mg of Salt Crystals Form A with MeOH in a50-mL volumetric flask.

Ultraviolet-Visible Spectrophotometry

The ultraviolet/visible spectrum for Salt Crystals Form A can be foundin FIG. 6. The spectra represent two different concentrations of SaltCrystals Form A in methanol. Two distinct maxima (227 nm

2 nm and 314 nm

2 nm) are found in the range of 200 nm to 500 nm. The molar extinctioncoefficient at 227 nm is calculated to be 43513 L*mol-1*cm-1. The molarextinction coefficient at 314 nm is calculated to be 4246 L*mol-1*cm-1.Calculation of Extinction Coefficient based on Salt Crystals Form A witha MW of 565.7. The spectra are recorded on a Cary 3 UV/Visiblespectrophotometer using a 1.0 cm quartz cell. The samples are preparedin duplicate for each maxima wavelength at concentrations of ca. 0.12mg/mL, 0.06 mg/mL for the maxima at 314 nm and ca. 0.012 mg/mL and 0.006mg/mL for the maxima at 227 nm to optimize the spectra at each maximaexamined. All samples are dissolved in methanol.

Residue on Ignition

Residue on ignition is performed according to USP 29/NF 24 (Supplement2) 2006, General Chapter <281>. A sample of ca. 1 g is accuratelyweighed directly into a platinum crucible that has been previouslyignited, cooled and weighed. The crucible is heated until the sample isthoroughly charred, then cooled. The residue is then moistened withapproximately 1 mL of concentrated sulfuric acid, heated gently untilwhite fumes no longer evolved, then ignited in a muffle furnace at600±50° C. until all the carbon within the crucible was consumed. Thesample is then cooled to room temperature in a desiccator. Aftercooling, the weight of residue is taken. The moistening with sulfuricacid, heating and igniting as before, using a 30 minute ignition period,is repeated, until two consecutive weighings of the residue does notdiffer by more than 0.5 mg. Results: Residue on Ignition=0.05%.

Elemental Analysis

The elemental analysis of sample Salt Crystals Form A is found to beconsistent with the empirical formula. Samples are analyzed in duplicateand oxygen is determined by difference.

Element Hydro- Nitro- Carbon gen gen Oxygen³ Fluorine Sulfur Percent65.48 6.63 7.44 11.15 3.39 5.92 Experimental Value¹ Percent 65.82 6.417.43 11.31 3.36 5.67 Theoretical Value² Percent −0.34 0.22 0.01 −0.160.03 0.25 Difference ¹Average (n = 2) ²ChemWindow V.5.1 ³Oxygendetermined by difference (Halogens interfere with the direct measurementof Oxygen)

X-Ray Powder Diffraction (XRPD)

The XRPD pattern of Salt Crystals Form A is shown in FIG. 7 along withsome of the more prominent 2θ values. Table 4 shows a listing of themore prominent 2θ angles, d-spacings and relative intensities.

XRPD data is collected at ambient temperature on a PANalytical X'Pertθ/θ diffractometer, operating with copper radiation at 45 kV and 40 mA,using an X'Celerator detector. Unmilled sample is placed on a flatstainless steel sample holder and leveled using a glass microscopeslide. Incident beam optics consists of ⅛° fixed divergence slit, ¼°fixed anti-scatter slit, 0.04 rad Soller slit and nickel filter tofilter out Kα2 radiation. Data is collected at 3° to 43° 2θ. A standardPC with Windows XP® operating system and PANalytical X'Pert DataCollector v 2.1a are used. X'Pert Data Viewer v 1.1a is used to plot thedata. The unit is calibrated annually using NBS silicon powder as astandard.

TABLE 4 Salt Crystals Form A Some of the More Prominent 2θ Angles,D-Spacing and Relative Intensities (Cu Kα Radation) POSITION HEIGHT FWHMRELATIVE (°2θ) (Cts) (°2θ) D-SPACING (Å) INTENSITY (%) 5.6811 11807.770.1658 15.54391 100.00 8.6140 1582.45 0.1671 10.37709 13.40 11.37501379.81 0.1863 7.77273 11.89 12.1088 3074.71 0.2072 7.30333 26.0413.3354 1329.25 0.1838 6.63416 11.26 15.7948 1845.19 0.2650 5.6062615.63 16.0419 2633.59 0.1568 5.52046 22.30 16.4461 976.96 0.5368 5.385708.27 17.0309 7890.92 0.2151 5.20205 66.83 17.2606 1283.83 4.0000 5.1333410.87 17.5531 1328.92 0.1966 5.04844 11.25 18.1581 2550.85 0.18714.88158 21.60 18.9968 2449.84 0.2219 4.66792 20.75 19.8889 3546.820.2456 4.46051 30.04 20.7510 559.67 0.0792 4.27711 4.74 21.6724 1855.280.1758 4.09730 15.71 22.5463 2825.63 0.2478 3.94041 23.93 23.48152226.62 0.1730 3.78556 18.86 23.7411 1604.25 0.1854 3.74475 13.5924.3006 2777.58 0.1798 3.65978 23.52 25.9394 874.95 0.3670 3.43216 7.4127.2321 673.90 0.2791 3.27209 5.71 28.3782 192.47 0.1700 3.14250 1.6328.9055 158.09 0.1331 3.08636 1.34 29.6695 493.21 0.2567 3.00860 4.1831.6106 374.66 0.1619 2.82814 3.17 32.2950 211.18 0.2236 2.76975 1.7934.8530 401.29 0.6501 2.57211 3.40 37.5435 283.20 0.1845 2.39373 2.4039.4972 264.36 0.2221 2.27971 2.24 40.2502 140.53 0.1475 2.23878 1.1940.8303 125.14 0.1353 2.20830 1.06

XRPD patterns of FIG. 7B are collected using a PANalytical X'Pert Prodiffractometer. An incident beam of Cu Kα radiation is produced using anOptix long, fine-focus source. An elliptically graded multilayer mirroris used to focus the Cu Kα X-rays of the source through the specimen andonto the detector. Data are collected and analysed using X'Pert Pro DataCollector software (v.2.2b). Prior to the analysis, a silicon specimen(NIST SRM 640c) is analyzed to verify the Si 111 peak position. Thespecimen is sandwiched between 3 μm thick films, analyzed intransmission geometry, and rotated to optimize orientation statistics. Abeam-stop is used to minimize the background generated by air scatting.Anti-scattering extension and He are not used. Soller slits are used forthe incident and diffracted beam to minimize axial divergence.Diffraction patterns are collected using a scanning position-sensitivedetector (X'Celerator) located 240 mm from the specimen. The dataacquisition parameters for each pattern are displayed above the image inthe Data section.

Differential Scanning Calorimetry (DSC)

The DSC scan for Salt Crystals Form A is shown in FIG. 8. The DSC scanshows a single endotherm with an onset temperature of 178.8° C., peaktemperature of 180.8° C., and ΔH=63.6 J/g. DSC measurements are madeusing a Perkin Elmer Pyris 1 DSC system equipped with an intracooler 2Prefrigeration unit. The Pyris 1 DSC is purged with nitrogen. Calibrationis performed prior to analysis using an Indium standard at a 10° C./minheating rate. Approximately 1.7 mg of sample is weighed on a Sartoriusmicrobalance in a tared Perkin Elmer 30 μL universal aluminum pan withholes in the lid, and sealed using a Perkin Elmer pan crimper press. Thesample is heated from room temperature to 300° C. at 10° C./min.

Thermo Gravimetric Analysis (TGA)

The TGA scan for Salt Crystals Form A is shown in FIG. 8. The TGAanalysis shows two regions of weight loss with a total weight loss of0.46% through 200° C. TGA measurements are collected using a PerkinElmer Pyris 1 TGA system purged with nitrogen. A 100-mg standard weightand Ni metal are used to verify balance and temperature calibrations,respectively. A sample of Salt Crystals Form A is heated from roomtemperature to 300° C. at 10° C./min.

Melting Point

A melting point determination is performed on an electro thermalcapillary melting point apparatus. The sample is heated from atemperature of 160° C. at a ramp rate of 2° C./min. Capillary meltingpoint data exhibit no true melting point as the material decomposes overthe region of 176.8 through 181.0° C. Thus the endotherm does notrepresent melting.

EXAMPLE 2 Preparation of the Salt Crystals Form B

Equip a 500 mL 3-neck round bottom flask with a mechanical stirrer,nitrogen inlet, drying tube and thermocouple. Dissolve the startingmaterial4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanonein toluenesulfonic acid addition salt (7.62 g, 0.01936 mol, 1equivalent) in Ethanol (200 proof (50 mL). Charge the solution ofstarting material in ethanol (step 2) to the flask. Addp-toluenesulfonic acid monohydrate (3.68 g, 0.01936 mol, 1 eq) in oneportion followed by charcoal (3 g). Heat the resulting mixture to 75-80°C. and stir at this temperature for 5-10 minutes. After this time removethe charcoal by filtration and wash the filter cake with Ethanol (3×30mL). Transfer the combined filtrate to a 1 L 3-neck round bottom flaskequipped with a mechanical stirrer, nitrogen inlet, drying the tube andthermocouple and placed in a cooling tub. Cool the solution to 0-5° C.Suspension forms during cooling. Dilute this suspension with heptane andstir at 0-5° C. for a minimum of 13 hours at this temperature. Collectthe solids by filtration. Wash the solids with cold Ethanol (20 mL, 0-5°C.) and then with heptane (room temperature, 50 mL). Dry the solids in avacuum oven at 35° C. to constant weight. Yield 7.2 g, 0.0127 mol,65.7%. HPLC: 96.4%. Chiral HPLC: de 100%. Melting point 182-183° C.

EXAMPLE 3 Preparation of the Salt Crystals Form B

Dissolve the starting material, 66-H-113 Peak 1 (9.32 g, 0.02368 mol, 1eq) in Ethanol (200 proof, 80 mL). Add charcoal (0.5 g) and stir theresulting mixture for 10-20 minutes at room temperature. After this timeremove charcoal by filtration. Wash the filter cake with Ethanol (2×30mL). Charge the solution of starting material in ethanol (from theprevious step) to a 1 L 3-neck round bottom flask with a mechanicalstiner, nitrogen inlet, drying tube and thermocouple the flask andplaced in a cooling tub. Add p-Toluenesulfonic acid monohydrate (4.51 g,0.02368 mol, 1 eq) in one portion at room temperature. Clear ambersolution forms. Soon solids stat to form. Cool the resulting suspensionto 0-5° C., stir for 1 hour at this temperature and then dilute withheptane (300 mL). Stir the suspension for a minimum of 13 hours at 0-5°C. After this time, obtain the solids by filtration (tan). Wash thesolids cold with heptane (room temperature, 50 mL). Dry the solids in avacuum oven at 35° C. to constant weight. Yield: 10.93 g, 0.01932 mol,81.59%.

Salt Crystals of Form B has the following XRPD: The XRPD pattern of SaltCrystals Form B is shown in FIG. 9. Table 5 shows a listing of the moreprominent 2θ angles, d-spacings and relative intensities.

TABLE 5 Pos. [°2Th.] Height [cts] FWHM [°2Th.] d-spacing [Å] Rel. Int.[%] 4.1373 3800.46 0.1299 21.35763 83.44 5.6541 3600.03 0.1299 15.6308879.04 8.2430 526.80 0.3897 10.72658 11.57 10.3839 1089.03 0.1299 8.5193723.91 11.3760 389.27 0.1624 7.77853 8.55 12.1103 1193.49 0.1948 7.3084426.20 13.3099 544.61 0.1624 6.65232 11.96 14.1235 732.42 0.1299 6.2708816.08 14.4743 583.24 0.1624 6.11969 12.81 14.8763 797.18 0.1299 5.9552017.50 15.3532 1091.73 0.1624 5.77130 23.97 15.8535 1531.27 0.29225.59028 33.62 16.4465 1139.43 0.1948 5.39000 25.02 17.0544 4554.660.1948 5.19923 100.00 17.9466 668.96 0.3897 4.94274 14.69 18.1622 884.320.1299 4.88454 19.42 18.6277 693.40 0.1299 4.76350 15.22 18.9621 714.430.1624 4.68024 15.69 19.8255 884.11 0.2598 4.47833 19.41 20.3507 2433.400.1624 4.36392 53.43 20.6196 1910.18 0.2598 4.30762 41.94 21.6034 604.410.2598 4.11363 13.27 22.4973 1188.22 0.2598 3.95215 26.09 23.4609 494.321.0391 3.79196 10.85 24.3083 1191.59 0.1299 3.66167 26.16 25.1377 399.770.2598 3.54270 8.78 26.0351 473.87 0.2273 3.42260 10.40 27.2489 970.430.1624 3.27282 21.31 29.0199 91.17 0.6494 3.07701 2.00 31.5733 191.510.2598 2.83374 4.20 35.0279 94.76 1.0391 2.56178 2.08 37.6449 72.130.5196 2.38949 1.58 39.4614 89.16 0.5845 2.28359 1.96

EXAMPLE 4 Preparation of the Solid Salt or Salt Crystals of the PresentInvention

Dissolve the starting material, 66-H-113 Peak 1 (5.28 g, 0.01342 mol, 1eq) in Ethanol (200 proof, 35 mL). After this time, remove the charcoalby filtration. Wash the filter cake with 1 Ethanol (2×15 mL). Charge thesolution of starting material in ethanol (from the previous step) to a500 in L 3-neck round bottom flask equipped with a mechanical stirrer,nitrogen inlet, drying tube and thermocouple. The flask is placed in acooling tub. Add p-Toluenesulfonic acid monohydrate (4.51 g, 0.02368mol, 1 eq) in one portion at room temperature. Clear dark amber solutionforms. Soon solids start to form. Cool the resulting suspension to 0-5°C. stir for 1 hour at this temperature and then dilute with heptane (200mL). Stir the suspension for a minimum of 13 hours at 0-5′C. After thistime remove the solids by filtration (tan). Wash the solids cold withheptane (room temperature, 40 mL). Dry the solids in a vacuum oven at35° C. to constant weight. Yield: 5.95 g, 0.010617 mol, 78.37%

EXAMPLE 5 Preparation of the Solid Salt or Salt Crystals of the PresentInvention

Crude free base is dissolved in EtOH (3000 mL), and is transferred to a12 L, 3-necked, round-bottomed flask equipped with a mechanical stirrer,a N₂ inlet, and a temperature probe. To the stirred solution is thenadded 178.3 g of pTSA monohydrate (0.94 mol, 1 equiv relative to thecrude free base). The batch is stirred at rt for ca. 1 h, and then theinternal temperature is reduced to 2 to 4° C. with an ice bath. Thebatch is stirred at 2 to 4° C. for another 1 h, and the batch becomes abrownish white slurry. To the batch is then added heptane (6000 mL)through an addition funnel slowly in ca. 3 h. The resultant mixture isstirred at 2 to 4° C. for another 1 h, and is stored in a dark cold roomfor ca. 15 h. The batch is then filtered, and the solid is rinsed withheptane (1000 mL). After drying in a vacuum oven at 35 to 40° C. for 4h, 345.8 g (61% yield) of a tan to brown solid was obtained. HPLCanalysis showed the desired product at 96.9% purity. LC-MS analysisshowed a major peak with M/e=394 (M+1). Chiral HPLC analysis showed thedesired enantiomer (first eluting peak) with ca. 99.7% e.e. ¹H NMR(CDCl₃, 300 MHz) δ 2.12-2.32 (m, 4H), 2.35 (s, 3H), 2.52-2.70 (m, 2H),2.80-2.94 (m, 1H), 2.90 (s, 3H), 3.02-3.24 (m, 5H), 3.26-3.42 (m, 4H),3.50-3.76 (m, 4H), 6.48 (d, J=7.8 Hz, 1H), 6.55 (d, J=7.2 Hz, 1H), 6.74(t, J=7.5 Hz, 1H), 7.04-7.14 (m, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.78 (dd,J=6.3 Hz, J′=1.5 Hz, 2H),7.92-7.98 (m, 2H), 10.60 (bs, 1H).

The invention claimed is:
 1. A4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanonetoluenesulfonic acid addition salt crystal form, wherein said saltcrystal form exhibits an X-ray powder diffraction pattern comprising atleast two peaks selected from the group consisting of 5.68°, 12.11°,16.04°, 17.03°, 18.16°, 19.00°, 21.67°, 22.55°, 23.48° and 24.30°±0.2°2θ.
 2. A pharmaceutical composition comprising the salt crystal formaccording to claim 1, as active ingredient, together with apharmaceutically acceptable diluent or carrier.